PROJECT SUMMARY Children with sickle cell anemia (SCA) suffer from complications that lead to significantly reduced physical functioning and exercise capacity. Despite the known benefits of regular physical activity across the lifespan, evidence-based recommendations for exercise prescription do not exist for children with SCA. Inflammation and endothelial dysfunction represent major contributors to disease pathophysiology and complications in SCA. For many children with SCA, the health benefits of physical activity are unrealized due to concerns that the well-described inflammatory effects of acute exercise may precipitate or exacerbate complications such as vaso-occlusive pain or exercise-induced bronchoconstriction (EIB). We have previously shown that compared to controls without SCA, children with SCA have 30% lower fitness levels and engage less often in vigorous physical activity and organized sports. However, children with SCA tolerate maximal cardiopulmonary exercise testing (CPET) without adverse effects and show similar patterns in their acute inflammatory response to maximal CPET. Although our preliminary data suggest that increasing physical activity may be beneficial rather than harmful in children with SCA, the pro-inflammatory effects associated with repeated bouts of moderate to vigorous exercise remain poorly understood. Our long term goal is to address the safety and health impact of regular exercise in children with SCA. For this proposal, we will evaluate the effect of acute exercise and exercise intensity on circulating systemic pro-inflammatory mediators and airway bronchoconstriction in SCA. We hypothesize that regular exercise at moderate to vigorous intensity is safe for children with SCA and do not precipitate SCA-related symptoms. In this multicenter study, 70 non-asthmatic children with SCA and 70 controls without SCA will first undergo maximal CPET, then be randomized to exercise challenge by controlled intensity interval training (CIIT) at either moderate or vigorous intensity (8 exercise bouts at 50-55% or 80-85% peak workload, respectively). Our Aims are to: 1) Determine the influence of exercise intensity on the acute inflammatory response to exercise, defined by an increase in soluble vascular cell adhesion molecule (VCAM) and other adhesion molecules, and 2) Define the effect of moderate to vigorous exercise on forced expiratory volume in 1 second (FEV1) and acute bronchoconstriction in children with SCA. We will also explore exercise- induced changes in gene and microRNA expression in peripheral blood mononuclear cells as well as the role of hyperventilation in bronchoconstriction using eucapnic voluntary hyperventilation testing. For the first time in SCA, our group of investigators in hematology, exercise science and exercise immunology will provide the critical prerequisite toward developing evidence-based guidelines for exercise prescription as a transformative strategy to maintain physical functioning and health in children with SCA. Our work would also offer insight into the clinical, physiologic and molecular basis of the exercise inflammatory response in SCA. Importantly, these data will inform the design of safe training regimens for future clinical trials of exercise in this population.